This invention relates to liposomal compositions and methods of using such compositions for treating neoplasia and for inhibiting angiogenesis.
Many anticancer or antineoplastic drugs have been encapsulated in liposomes. These include alkylating agents, nitrosoureas, cisplatin, antimetabolites, and anthracyclines. Studies with liposomes containing anthracycline antibiotics have clearly shown reduction of cardiotoxicity and dermal toxicity and prolonged survival of tumor bearing animals compared to controls receiving free drug.
Liposomal anticancer drugs modify drug pharmacokinetics as compared to their free drug counterpart. For a liposomal drug formulation, drug pharmacokinetics will be largely determined by the rate at which the carrier is cleared from the blood and the rate at which the drug is released from the carrier. Considerable efforts have been made to identify liposomal carrier compositions that show slow clearance from the blood and long-circulating carriers have been described in numerous scientific publications and patents. Efforts have also been made to control drug leakage rates from liposomal carriers, using for example, transmembrane potential to control release.
Therapeutic camptothecins, such as Topotecan (9-dimethylaminomethyl-10-hydroxy-camptothecin; Hycamtin™), and Irinotecan, are a semi-synthetic, water soluble derivative of camptothecin, an alkaloid extracted from the stem wood of the Chinese tree Camptotheca acuminata (Wall, et al., J. Am. Chem. Soc. 88:3888-3890 (1966)). Camptothecins belong to the topoisomerase inhibitor class of antineoplastic agents, specifically inhibiting the action of the nuclear enzyme topoisomerase I which is involved in DNA replication (Hsiang, et al., Cancer Res. 48:1722-1726 (1988)). As such, topotecan exhibits a cell cycle-specific mechanism of action, acting during S-phase (DNA replication) to cause irreversible double strand breaks in DNA that ultimately lead to G2 cell cycle arrest and apoptosis. In the free form, the drug has a broad spectrum of activity against a range of tumor cell lines and murine allograft and human xenograft tumor models (McCabe, F. L. et al., Cancer Invest 12:308-313 (1994); Emerson, et al., Cancer Res. 55:603-609 (1995); Thompson, Biochim. Biophys. Acta 1400:301-319 (1998); Ormrod, et al., Drugs 58:533-551 (1999); Hardman, et al., Anticancer Res. 19:2269-2274 (1999)). More recently, evidence has emerged that topotecan has strong anti-angiogenic properties that may contribute to its anti-tumor mechanism of action (O'Leary, et al., Clin. Cancer Res. 5:181-187 (1999); Clements, et al., Cancer Chemother. Pharmacol. 44:411-416 (1999)). All these treatments are associated with dose-limiting toxicity such as non-cumulative myelosuppression leading to anaemia, neutropenia and thrombocytopenia, and gastrointestinal-related toxicity, including mucositis and diarrhea. Clinically, topotecan has been approved for second-line therapy in ovarian and small cell lung cancer (SCLC) and is currently the focus of extensive clinical evaluation.
Lipid formulations of camptothecins have been proposed as therapeutic agents (see, U.S. Pat. No. 5,552,156 and PCT Publication No. WO 95/08986. However, not all lipid formulations are equal for drug delivery purposes and extensive research continues into formulations which demonstrate preferred characteristics for drug loading and storage, drug administration, pharmacokinetics, biodistribution, leakage rates, tumor accumulation, toxicity profile, and the like. With camptothecins, the field is further complicated because dose limiting toxicities in humans may be 10-fold lower than in mice (Erickson-Miller, et al., Cancer Chemother. Pharmacol. 39:467-472 (1997)).
Improved liposomal formulations of antineoplastic agents could prove very useful. It is an object of the instant invention to provide lipid formulated antineoplastic agents having novel clinical utility.